Terpenoidic derivatives useful as antitumor agents

ABSTRACT

A method of treating tumors in a human or animal by administering thereto a pharmaceutically effective amount of a Sarcodictyin compound selected from Sarcodictyin A, B, C, D, E, and F. Sarcodictyin A has the formula (-)-(4R,4aR,7R,10S,11S,12aR,1Z,5E,8Z)-7,10-Epoxy3,4,4a,7,10,11,12,12a-octahydro-7-hydroxy-6-(methoxy-carbonyl)-1,10- dimethyl-4-(1-methylethyl)benzo cyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl) acrylate (Sarcodictyin A).

This application is a 371 of PCT/EP96/01688 filed Apr. 23, 1996.

The present invention relates to terpenoidic derivatives, known in theart as Sarcodictyins (Helvetica Chimica Acta Vol. 70, 1987, 2019-2027and Helvetica Chimica Acta, Vol. 71, 1988, 964-976), which can be usefulas therapeutic agents.

A possible therapeutic application of the Sarcodictyins mentioned in thepresent application was not reported earlier.

In particular, according to the present invention, Sarcodictyins, inview of their cytotoxic activity, can be of use as therapeuticantineoplastic agents in the treatment of cancers in human or animalbeings.

Accordingly, the present invention refers to a compound selected fromthe group consisting of:

(-)-(4R,4aR,7R,10S,11S,12aR,1Z,5E,8Z)-7,10-Epoxy-3,4,4a,7,10,11,12,12a-octahydro-7-hydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4yl) acrylate (SarcodictyinA);

(-)-(4R,4aR,7R,10S,1S,12aR,1Z,5E,8Z)-7,10-Epoxy-6-(ethoxycarbonyl)-3,4,4a,7,10,11,12,12a-octahydro-7-hydroxy-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H,imidazol-4-yl)acrylate(Sarcodictyin B);

(-)-(3R,4S,4aS,7S,10R,11R,12aS,1Z,5E,8Z)-7,10-Epoxy-3,4,4a,7,10,11,12,12a,octahydro-3,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl) acrylate(Sarcodictyin C);

(-)-(3R,4S,4aS,7S,10R,11R,12aS,1Z,5E,8Z)-3-Acetoxy-7,10-epoxy-3,4,4a,7,10,11,12,12a-octahydro-7-hydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl) acrylate(Sarcodictyin D);

(+)-(3R,4S,4aS,7S,10R,11R,12aS,1Z,5E,8Z)-7,10-Epoxy-3,4,4a,7,10,11,12,12a-octahydro-3,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(Z)-3-(1-Methyl-1H-imidazol-4-yl) acrylate(Sarcodictyin E); and

(+)-(1R,4R,4aR,7R,10S,11S,12aR,2Z,5E,8Z)-7,10-Epoxy-1,4,4a,7,10,11,12,12a-octahydro-1,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl) acrylate(Sarcodictyin F);

for use as a therapeutic agent.

The structural formulae of the above listed compounds is reported inTable 1 below, with reference to the following formulae: ##STR1##

                  TABLE 1    ______________________________________    COMPOUND      (A)      R.sub.1 R.sub.2                                        R.sub.3    ______________________________________    Sarcodictyin A                  (A.sub.1)                           Me      H    (E)u    Sarcodictyin B                  (A.sub.1)                           Et      H    (E)u    Sarcodictyin C                  (A.sub.1)                           Me      OH   (E)u    Sarcodictyin D                  (A.sub.1)                           Me      OAC  (E)u    Sarcodictyin E                  (A.sub.1)                           Me      OH   (Z)u    Sarcodictyin F                  (A.sub.2)                           Me      OH   (E)u    ______________________________________

In the above Table 1:

the symbol Me means methyl;

the symbol Et means ethyl;

the Symbol OAc means OCOCH₃.

the symbols (E)u and (Z)u represent, respectively, the (E) and (Z)urocanoyl moiety of formula ##STR2##

In particular, the above reported Sarcodictyins A to F may be useful astherapeutic agents in the treatment of cancers in human or animalbeings, by virtue of their cytotoxic, antitumor activity. The cancer maybe selected from sarcomas, carcinomas, lymphomas, neuroblastomas,melanomas, myelomas, Wilms tumor, leukemias and adenocarcinomas. TheSarcodictyins of the invention may be obtained by isolation from theMediterranean Stoloniferan Coral "Sarcodictyon Roseum" (Rolandia rosea)(Forbes 1847) according to the method reported in Helvetica Chimica ActaVol. 70, 1987, page,2025.

The biolgical activity of the Sarcodictyins of the invention wasdemonstrated by (a) "in vitro" test to evaluate their activity inpromoting the tubulin assembly and (b) "in vitro" test to evaluate theircytotoxic activity both on L 1210 cells and L 1210 cells resistant toDoxorubicin (L 1210/Dx).

As an example, the activity of Sarcodictyin A (internal code FCE 29123)and Sarcodictyin C (internal code FCE 29119) was evaluated according tothe methods described in tests (a) and (b).

(a) Tubulin Assembly Test

Calf brain tubulin was prepared by two cycles of assembly-disassembly(Shelanski M. L., Gaskin F. and Cantor C. R., Proc. Natl.Acad.Sci.U.S.A. 70, 765-768, 1973; and stored in liquid nitrogen in MAB (0.1MMES, 2.5 mM EGTA, 0.5 mM MgSO₄, 0.1 mM EDTA, 0.1 mM DTT, pH 6.4).

All the experiments were carried out on protein stored for less than 4weeks.

Before each experiment, tubulin was kept 30 min at 4° C. Assembly wasmonitored by the method of Gaskin et al. (Gaskin F., Cantor C. R. andShelanski M. L., J.Molec.Biol. 89, 737-758, 1974).

The cuvette (1 cm path) containing tubulin (1 mg/ml) and 1 mM GTP wasshifted to 37° C. and continuous turbidity measurements were made at 340nm on a Perkin-Elmer 557 double wavelength, double beamspectrophotometer equipped with an automatic recorder and athermostatically regulated sample chamber.

After 30 minutes, 4 mM CaCl₂ was added and depolymerisation was measuredfor 10 minutes as decreased turbidity.

At regular intervals of 15 minutes scaled doses of the tested compoundswere added and variations in the turbidity were monitored.

Data are expressed as percentage of repolymerization induced by thetested compounds.

The obtained results are reported in Table 2

                  TABLE 2    ______________________________________    COMPOUND      dosage (μM)                            tubulin assembly (%)    ______________________________________    Sarcodictyin A                  4         70    (FCE 29123)   40        162    Sarcodictyin C                  3.9       112    (FCE 29119)   39        173    ______________________________________

The above tabulated data clearly demonstrate that the testedSarcodictyins are able to promote tubulin repolymerization even in thepresence of CaCl₂ which usually inhibits tubulin assembly.

As it is well known in the art, microtubules are among the moststrategic subcellular targets of anticancer chemotherapeutics (Rowinskyet al., Review, Vol. 82, No. 15, Aug. 1, 1990).

Unlike classical antimicrotubule agents like colchicine and the vincaalkaloids which induce depolymerization of microtubules, Sarcodictynsseem to possess a mechanism of action similar to that of Taxol, one ofthe most interesting anticancer agents emerged from the screening ofnatural products, by inducing tubulin polymerization and formingextremely stable and nonfunctional microtubules.

Sarcodictyins can therefore be useful as therapeutic antineoplasticagents in the treatment of cancers in human or animal beings, in view oftheir ability to catalize rapid microtubule formation and stabilizationwhich cause suspension of cellular division in the tumor cells.

(b) Cell Cultures and Drug Sensitivity Assay

L1210 and L1210/DX (Doxorubicin resistant) murine leukemia cell lineswere grown in vitro as a stationary suspension culture in RPMI 1640medium (GIBCO, Grand island, N.Y.) supplemented with 10% fetal calfserum (Flow, Irwine, UK), 2 mM L-glutamine (Gibco Europe, Glasgow, UK),10 μM β-mercaptoethanol, 100 Units/ml penicillin and 100 μg/mlstreptomycin.

Exponentially growing cells were seeded (1×10⁵ cell/ml) in12-well/plates (Costar, Cambridge, Mass.) and various concentrations oftested compounds were added immediately after seeding.

The plates were incubated at 37° C. in a humidified, 5% CO₂ atmospherefor 48 hr.

Inhibition of cell growth was evaluated by counting surviving cells in aZBI Coulter Counter (Hialeah, Fla.). The 50% inhibitory concentration(IC₅₀) was calculated on the derived concentration-response curve. Foreach tested compound concentration, duplicate cultures were used.

The obtained results are reported on Table 3

                  TABLE 3    ______________________________________               ID.sub.50 (nM)*    Compound     L1210       L1210/DX   R.I    ______________________________________    Sarcodictyin A                 539.2 ± 97.7                             754.5 ± 80.3                                        1.4    (FCE 29123)    Sarcodictyin C                 408.5 ± 21.3                             5787.0 ± 182.6                                        14.2    (FCE 29119)    ______________________________________     *48 h treatment     ##EQU1##

As evident from the above tabulated data, Sarcodictyins exhibit a good"in vitro" cytotoxic activity both on L1210 and L1210 cells resistant toDoxorubicin (L1210/Dx).

In view of their effectiveness on L 1210/DX cells, the Sarcodictyins canbe useful in the treatment of a tumor resistant to a chemotherapeuticagent, such as, e.g., an anthracycline glycoside, in particularDoxorubicin.

A human or animal being can be treated by a method which comprises theadministration thereto of a pharmaceutically effective amount of acompound selected from Sarcodictyin A, Sarcodictyin B. Sarcodictyin C,Sarcodictyin D, Sarcodictyin E and Sarcodictyin F.

The condition of the human or animal being can thereby be improved.

The Sarcodictyins of the invention can be administered in a variety ofdosage forms, e.g. orally, in the form of tables, capsules, sugar orfilm coated tablets, liquid solutions or suspensions; rectally in theform of suppositories; parenterally, e.g. intramuscularly, or byintravenous injection or infusion.

The dosage depends on the age, weight, conditions of the patient and onthe administration route; for example, the dosage adopted for oraladministration to adult humans, e.g., for the representative compound ofthe invention FCE 29213 (Sarcodictyin A) may range from about 0.01 g toabout 1 g per day.

The invention includes also pharmaceutical compositions comprising aSarcodictyin of the invention as an active principle in association witha pharmaceutically acceptable excipient (which can be a carrier or adiluent).

The pharmaceutical compositions containing the compounds of theinvention are usually prepared following conventional methods and areadministered in a pharmaceutically suitable form.

For example, the solid oral forms may contain, together with the activecompound, diluents, e.g. lactose, destrose, saccharose, cellulose, cornstarch or potato starch; lubricants, e.g. silica, talc, stearic acid,magnesium or calcium stearate, and/or polyethylene glycols; bindingagents, e.g. starches, arabic gums, gelatin, methylcellulose,carboxymethycellulose or polyvinyl pyrrolidone; disaggregating agents,e.g. a starch, alginic acid, alginates or sodium starch glycolate;effervescing mixtures; dyestuffs; sweeteners; wetting agents such aslecithin, polysorbates, laurylsulphates; and, in general, non-toxic andpharmacologically inactive substances used in pharmaceuticalformulations.

Said pharmaceutical preparations may be manufactured in known manner,for example by means of mixing, granulating, tabletting, sugar-coating,or film-coating processes.

The liquid dispersions for oral administration may be, e.g., syrups,emulsions and suspensions.

The syrups may contain as carrier, for example, saccharose or saccharosewith glycerine and/or mannitorl and/or sorbitol.

The suspensions and the emulsions may contain as carrier, for example, anatural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethyl-cellulose, or polyvinyl alcohol.

The suspension or solution for intramuscular injections may contain,e.g., together with the active compound, a pharmaceutically acceptablecarrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g.propylene glycol, and, if desired, a suitable amount of lidocainehydrochloride.

The solutions for intravenous injections or infusion may contain ascarrier, for example, sterile water or preferably they may be in theform of sterile, acqueous, isotonic saline solutions.

The suppositories may contain together with the active compound apharmaceutically acceptable carrier, e.g. cocoa butter, polyethyleneglycol, a polyoxyethylene sorbitan fatty acid ester surfactant orlecithin.

We claim:
 1. A method of enhancing tubulin assembly comprisingcontacting tubulin with an effective amount of a Sarcodictyin compoundselected from the group consisting ofa)(-)-(4R,4aR,7R10S,11S,12aR,1Z,5E,8Z)-7,10-Epoxy3,4,4a,7,10,11,12,12a-octahydro-7-hydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl) acrylate (SarcodictyinA); b)(-)-(4R,4aR,7R,10S,11S,12aR,1Z,5E,8Z)-7,10-Epoxy-6(ethoxycarbonyl)-3,4,4a,7,10,11,12,12a-octahydro-7-hydroxy-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H,imidazol-4-yl)acrylate(Sarcodictyin B); c)(-)-(3R,4S,4aS,7S,10R,11R,12aS,1Z,5E,8Z)-7,10-Epoxy-3,4,4a,7,10,11,12,12a,octahydro-3,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl)acrylate(Sarcodictyin C); d)(-)-(3R,4S,4aS,7S,10R,11R,12aS,1Z,5E,8Z)-3-Acetoxy7,10-epoxy-3,4,4a,7,10,11,12,12a-octahydro-7-hydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl)acrylate(Sarcodictyin D); e)(+)-(3R,4S,4aS,7S,10R,11R,12aS,1Z,5E,8Z)-7,10-Epoxy-3,4,4a,7,10,11,12,12a-octahydro-3,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(Z)-3-(1-Methyl-1H-imidazol-4-yl)acrylate(Sarcodictyin E); and f)(+)-(1R,4R,4aR,7R,10S,11S,12aR,2Z,5E,8Z)-7,10-Epoxy-1,4,4a,7,10,11,12,12a-octahydro-1,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl)acrylate(Sarcodictyin F).
 2. The method of claim 1 wherein said compound is(-)-(4R,4aR,7R,10S,11S,12aR,1Z,5E,8Z)-7,10-Epoxy3,4,4a,7,10,11,12,12a-octahydro-7-hydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl)acrylate (SarcodictyinA).
 3. The method of claim 1, wherein said compound is(-)-(4R,4aR,7R,10S,11S,12aR,1Z,5E,8Z)-7,10-Epoxy-6(ethoxycarbonyl)-3,4,4a,7,10,11,12,12a-octahydro-7-hydroxy-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H,imidazol-4-yl)acrylate(Sarcodictyin B).
 4. The method of claim 1, wherein said compound is(-)-(3R,4S,4aS,7S,10R,11R,12aS,1Z,5E,8Z)-7,10-Epoxy-3,4,4a,7,10,11,12,12a,octahydro-3,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl)acrylate(Sarcodictyin C).
 5. The method of claim 1, wherein said compound is(-)-(3R,4S,4aS,7S,10R,11R,12aS,1Z,5E,8Z)-3-Acetoxy-7,10-epoxy-3,4,4a,7,10,11,12,12a-octahydro-7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(Z)-3-(1-Methyl-1H-imidazol-4-yl)acrylate(Sarcodictyin D).
 6. The method of claim 1, wherein said compound is(+)-(3R,4S,4aS,7S,10R,11R,12aS,1Z,5E,8Z)-7,10-Epoxy-3,4,4a,7,10,11,12,12a-octahydro-3,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(Z)-3-(1-Methyl-1H-imidazol-4-yl)acrylate(Sarcodictyin E).
 7. The method of claim 1, wherein said compound is(+)-(1R,4S,4aR,7S,10R,11R,12aR,2Z,5E,8Z)-7,10-Epoxy-1,4,4a,7,10,11,12,12a-octahydro-1,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl)acrylate(Sarcodictyin F).
 8. A method of treating a tumor in a human or animalbeing having said tumor comprising administering a Sarcodictyin compoundto said human or animal being, wherein said Sarcodictyin is a compoundselected from the group consisting of:a)(-)-(4R,4aR,7R,10S,11S,12aR,1Z,5E,8Z)-7,10-Epoxy3,4,4a,7,10,11,12,12a-octahydro-7-hydroxy-6-(methoxy-carbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl)acrylate(Sarcodictyin A); b)(-)-(4R,4aR,7R,10S,11S,12aR,1Z,5E,8Z)-7,10-Epoxy-6(ethoxycarbonyl)-3,4,4a,7,10,11,12,12a-octahydro-7-hydroxy-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H,imidazol-4-yl)acrylate(Sarcodictyin B); c)(-)-(3R,4S,4aS,7S,10R,11R,12aS,1Z,5E,8Z)-7,10-Epoxy-3,4,4a,7,10,11,12,12a,octahydro-3,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl)acrylate(Sarcodictyin C); d)(-)-(3R,4S,4aS,7S,10R,11R,12aS,1Z,5E,8Z)-3-Acetoxy-7,10-epoxy-3,4,4a,7,10,11,12,12a-octahydro-7-hydroxy-6-(methoxycarbonyl)1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-(1H-imidazol-4yl)acrylate(Sarcodictyin D); e)(+)-(3R,4S,4aS,7S,10R,11R,12aS,1Z,5E,8Z)-7,10-Epoxy-3,4,4a,7,10,11,12,12a-octahydro-3,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(Z)-3-(1-Methyl-1H-imidazol-4-yl)acrylate(Sarcodictyin E); and f)(+)-(1R,4R,4aR,7R,10S,11S,12aR,2Z,5E,8Z)-7,10-Epoxy-1,4,4a,7,10,11,12,12a-octahydro-1,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl)acrylate(Sarcodictyin F).
 9. The method of claim 8, wherein said Sarcodictyincompound is(-)-(4R,4aR,7R,10S,11S,12aR,1Z,5E,8Z)-7,10-Epoxy3,4,4a,7,10,11,12,12a-octahydro-7-hydroxy-6-(methoxy-carbonyl)-1,10-dimethyl-4-(1-methylethyl)benzo cyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl)acrylate(Sarcodictyin A).
 10. The method of claim 8, wherein said Sarcodictyincompound is(-)-(4R,4aR,7R,10S,11S,12aR,1Z,5E,8Z)-7,10-Epoxy-6(ethoxycarbonyl)-3,4,4a,7,10,11,12,12a-octahydro-7-hydroxy-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H,imidazol-4-yl)acrylate (Sarcodictyin B).
 11. Themethod of claim 8, wherein said Sarcodictyin compound is(-)-(3R,4S,4aS,7S,10R,11R,12aS,1Z,5E,8Z)-7,10-Epoxy-3,4,4a,7,10,11,12,12a,octahydro-3,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl)acrylate(Sarcodictyin C).
 12. The method of claim 8, wherein said Sarcodictyincompound is(-)-(3R,4S,4aS,7S,10R,11R,12aS,1Z,5E,8Z)-3-Acetoxy7,10-epoxy-3,4,4a,7,10,11,12,12a-octahydro-7-hydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl)acrylate(Sarcodictyin D).
 13. The method of claim 8, wherein said Sarcodictyincompound is(+)-(3R,4S,4aS,7S,10R,11R,12aS,1Z,5E,8Z)-7,10-Epoxy-3,4,4a,7,10,11,12,12a-octahydro-3,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(Z)-3-(1-Methyl-1H-imidazol-4-yl)acrylate(Sarcodictyin E).
 14. The method of claim 8, wherein said Sarcodictyinis(+)-(1R,4R,4aR,7R,10S,11S,12aR,2Z,5E,8Z)-7,10-Epoxy-1,4,4a,7,10,11,12,12a-octahydro-1,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl)acrylate(Sarcodictyin F).
 15. The method of claim 8, wherein said tumor isresistant to a chemotherapeutic agent.
 16. The method of claim 15,wherein said chemotherapeutic agent is an anthracycline glycoside. 17.The method of claim 16, wherein said anthracycline glycoside isDoxorubicin.
 18. The method of claim 8 which comprises administering apharmaceutical composition comprising as an active ingredient a chemicalcompound selected from the group consisting of Sarcodictyin A,Sarcodictyin B, Sarcodictyin C, Sarcodictyin D, Sarcodictyin E andSarcodictyin F, said composition containing in addition to said activeingredient a non-toxic, pharmaceutically acceptable, inactive substanceselected from diluents, lubricants, binding agents, effervescingmixtures, dyestuffs, sweeteners, wetting agents, carriers and thickeningagents.
 19. A method as set forth in claim 18, wherein said compositionis in solid oral form and contains a diluent selected from the groupconsisting of lactose, dextrose, saccharose, cellulose, corn starch andpotato starch.
 20. A method as set forth in claim 18, wherein saidcomposition is a liquid suitable for oral administration and is in theform of a syrup, emulsion or suspension.
 21. The method of claim 18,wherein said pharmaceutical composition is in the form of a suspensionor solution suitable for injection and contains a pharmaceuticallyacceptable liquid carrier selected from the group consisting of sterilewater, olive oil, ethyl oleate and glycols.
 22. The method as set forthin claim 18, wherein said composition is in the form of a suppositoryand contains a carrier selected from the group consisting of cocoabutter, polyethylene glycol, polyoxyethylene sorbitan fatty acid estersurfactant and lecithin.